Tau is an intrinsically disordered protein that accumulates in fibrillar aggregates in neurodegenerative diseases. The misfolding of tau can be understood as an equilibrium between different states and their propensity to form higher-order fibers, which is affected by several factors. First, modulation of the biochemical state of tau due to ionic conditions, post-translational modifications, cofactors, and interacting molecules or assemblies can affect the formation and structure of tau fibrils. Second, cellular processes impact tau aggregation through modulating stability, clearance, disaggregation, and transport. Third, through interactions with glial cells, the neuronal microenvironment can affect intraneuronal conditions with impacts on tau fibrilization and toxicity. Importantly, tau fibrils propagate through the brain via a “prion-like” manner, contributing to disease progression. This review highlights the biochemical and cellular pathways that modulate tau aggregation and discusses implications for pathobiology and tau-directed therapeutic approaches.
{"title":"Diverse influences on tau aggregation and implications for disease progression","authors":"Meaghan Van Alstyne, James Pratt, Roy Parker","doi":"10.1101/gad.352551.124","DOIUrl":"https://doi.org/10.1101/gad.352551.124","url":null,"abstract":"Tau is an intrinsically disordered protein that accumulates in fibrillar aggregates in neurodegenerative diseases. The misfolding of tau can be understood as an equilibrium between different states and their propensity to form higher-order fibers, which is affected by several factors. First, modulation of the biochemical state of tau due to ionic conditions, post-translational modifications, cofactors, and interacting molecules or assemblies can affect the formation and structure of tau fibrils. Second, cellular processes impact tau aggregation through modulating stability, clearance, disaggregation, and transport. Third, through interactions with glial cells, the neuronal microenvironment can affect intraneuronal conditions with impacts on tau fibrilization and toxicity. Importantly, tau fibrils propagate through the brain via a “prion-like” manner, contributing to disease progression. This review highlights the biochemical and cellular pathways that modulate tau aggregation and discusses implications for pathobiology and tau-directed therapeutic approaches.","PeriodicalId":12591,"journal":{"name":"Genes & development","volume":"19 1","pages":""},"PeriodicalIF":10.5,"publicationDate":"2025-03-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143666280","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Metastasis and therapy resistance drive cancer-related deaths, with melanoma cells exhibiting phenotypic plasticity that allows them to switch between proliferative and invasive states. In this issue of Genes & Development, Chocarro-Calvo and colleagues (doi:10.1101/gad.351985.124) reveal that oleic acid activates AXL, a receptor involved in metastasis and therapy resistance, linking lipid metabolism to melanoma aggressiveness. They demonstrate that MITFLow/AXLHigh cells induce lipolysis in human adipose tissue via WNT5A secretion, compensating for lipid synthesis deficiencies. The study highlights distinct lipid uptake mechanisms in melanoma subpopulations and suggests that targeting AXL-driven lipid uptake could provide therapeutic opportunities. These findings have broad implications, indicating that metabolic cues influence AXL activation in other cancers.
{"title":"From fat to fear: how lipid powers cancer spread","authors":"Lionel Larue","doi":"10.1101/gad.352753.125","DOIUrl":"https://doi.org/10.1101/gad.352753.125","url":null,"abstract":"Metastasis and therapy resistance drive cancer-related deaths, with melanoma cells exhibiting phenotypic plasticity that allows them to switch between proliferative and invasive states. In this issue of <em>Genes & Development</em>, Chocarro-Calvo and colleagues (doi:10.1101/gad.351985.124) reveal that oleic acid activates AXL, a receptor involved in metastasis and therapy resistance, linking lipid metabolism to melanoma aggressiveness. They demonstrate that MITF<sup>Low</sup>/AXL<sup>High</sup> cells induce lipolysis in human adipose tissue via WNT5A secretion, compensating for lipid synthesis deficiencies. The study highlights distinct lipid uptake mechanisms in melanoma subpopulations and suggests that targeting AXL-driven lipid uptake could provide therapeutic opportunities. These findings have broad implications, indicating that metabolic cues influence AXL activation in other cancers.","PeriodicalId":12591,"journal":{"name":"Genes & development","volume":"58 1","pages":""},"PeriodicalIF":10.5,"publicationDate":"2025-03-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143627401","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Shawn C. Massoni, Nicola J. Evans, Ingo Hantke, Colleen Fenton, James H. Torpey, Katherine M. Collins, Ewelina M. Krysztofinska, Janina H. Muench, Arjun Thapaliya, Santiago Martínez-Lumbreras, Sé Hart Ferrell, Celia Slater, Xinyue Wang, Ruth Fekade, Sandra Obwar, Siyu Yin, Alishba Vazquez, Christopher B. Prior, Kürşad Turgay, Rivka L. Isaacson, Amy H. Camp
Bacterial protein degradation machinery consists of chaperone–protease complexes that play vital roles in bacterial growth and development and have sparked interest as novel antimicrobial targets. ClpC–ClpP (ClpCP) is one such chaperone–protease complex, recruited by adaptors to specific functions in the model bacterium Bacillus subtilis and other Gram-positive bacteria, including the pathogens Staphylococcus aureus and Mycobacterium tuberculosis. Here we have identified a new ClpCP adaptor protein, MdfA (metabolic differentiation factor A; formerly YjbA), in a genetic screen for factors that help drive B. subtilis toward metabolic dormancy during spore formation. A knockout of mdfA stimulates gene expression in the developing spore, while aberrant expression of mdfA during vegetative growth is toxic. MdfA binds directly to ClpC to induce its oligomerization and ATPase activity, and this interaction is required for the in vivo effects of mdfA. Finally, a cocrystal structure reveals that MdfA binds to the ClpC N-terminal domain at a location analogous to that on the M. tuberculosis ClpC1 protein where bactericidal cyclic peptides bind. Altogether, our data and that of an accompanying study by Riley and colleagues support a model in which MdfA induces ClpCP-mediated degradation of metabolic enzymes in the developing spore, helping drive it toward metabolic dormancy.
{"title":"MdfA is a novel ClpC adaptor protein that functions in the developing Bacillus subtilis spore","authors":"Shawn C. Massoni, Nicola J. Evans, Ingo Hantke, Colleen Fenton, James H. Torpey, Katherine M. Collins, Ewelina M. Krysztofinska, Janina H. Muench, Arjun Thapaliya, Santiago Martínez-Lumbreras, Sé Hart Ferrell, Celia Slater, Xinyue Wang, Ruth Fekade, Sandra Obwar, Siyu Yin, Alishba Vazquez, Christopher B. Prior, Kürşad Turgay, Rivka L. Isaacson, Amy H. Camp","doi":"10.1101/gad.352498.124","DOIUrl":"https://doi.org/10.1101/gad.352498.124","url":null,"abstract":"Bacterial protein degradation machinery consists of chaperone–protease complexes that play vital roles in bacterial growth and development and have sparked interest as novel antimicrobial targets. ClpC–ClpP (ClpCP) is one such chaperone–protease complex, recruited by adaptors to specific functions in the model bacterium <em>Bacillus subtilis</em> and other Gram-positive bacteria, including the pathogens <em>Staphylococcus aureus</em> and <em>Mycobacterium tuberculosis</em>. Here we have identified a new ClpCP adaptor protein, MdfA (metabolic differentiation factor A; formerly YjbA), in a genetic screen for factors that help drive <em>B. subtilis</em> toward metabolic dormancy during spore formation. A knockout of <em>mdfA</em> stimulates gene expression in the developing spore, while aberrant expression of <em>mdfA</em> during vegetative growth is toxic. MdfA binds directly to ClpC to induce its oligomerization and ATPase activity, and this interaction is required for the in vivo effects of <em>mdfA</em>. Finally, a cocrystal structure reveals that MdfA binds to the ClpC N-terminal domain at a location analogous to that on the <em>M. tuberculosis</em> ClpC1 protein where bactericidal cyclic peptides bind. Altogether, our data and that of an accompanying study by Riley and colleagues support a model in which MdfA induces ClpCP-mediated degradation of metabolic enzymes in the developing spore, helping drive it toward metabolic dormancy.","PeriodicalId":12591,"journal":{"name":"Genes & development","volume":"89 1","pages":""},"PeriodicalIF":10.5,"publicationDate":"2025-03-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143627430","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Developing spores (forespores) of Bacillus subtilis lack TCA cycle and amino acid and ribonucleotide biosynthetic enzymes but still carry out much macromolecular synthesis to make a spore—but how and why? Work by many showed that the mother cell supplies ATP and metabolites to the forespore via a feeding tube. Two recent studies in this issue of Genes & Development, by Massoni and colleagues (doi:10.1101/gad.352498.124) and Riley and colleagues (doi:10.1101/gad.352535.124), now show that specific metabolic enzymes disappear early in forespore development via proteolysis by ClpCP and a forespore-specific activator termed MdfA. Future work may clarify how this proteolysis recognizes specific metabolic enzymes and determine the advantages of this overall process for spores.
{"title":"Where and why have so many metabolic enzymes gone from developing spores of Bacillus subtilis?","authors":"Peter Setlow","doi":"10.1101/gad.352755.125","DOIUrl":"https://doi.org/10.1101/gad.352755.125","url":null,"abstract":"Developing spores (forespores) of <em>Bacillus subtilis</em> lack TCA cycle and amino acid and ribonucleotide biosynthetic enzymes but still carry out much macromolecular synthesis to make a spore—but how and why? Work by many showed that the mother cell supplies ATP and metabolites to the forespore via a feeding tube. Two recent studies in this issue of <em>Genes & Development</em>, by Massoni and colleagues (doi:10.1101/gad.352498.124) and Riley and colleagues (doi:10.1101/gad.352535.124), now show that specific metabolic enzymes disappear early in forespore development via proteolysis by ClpCP and a forespore-specific activator termed MdfA. Future work may clarify how this proteolysis recognizes specific metabolic enzymes and determine the advantages of this overall process for spores.","PeriodicalId":12591,"journal":{"name":"Genes & development","volume":"14 1","pages":""},"PeriodicalIF":10.5,"publicationDate":"2025-03-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143627425","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Eammon P. Riley, Jelani A. Lyda, Octavio Reyes-Matte, Joseph Sugie, Iqra R. Kasu, Eray Enustun, Emily G. Armbruster, Sumedha Ravishankar, Rivka L. Isaacson, Amy H. Camp, Javier Lopez-Garrido, Kit Pogliano
Bacillus subtilis sporulation entails a dramatic transformation of the two cells required to assemble a dormant spore, with the larger mother cell engulfing the smaller forespore to produce the “cell within a cell” structure that is a hallmark of endospore formation. Sporulation also entails metabolic differentiation, whereby key metabolic enzymes are depleted from the forespore but maintained in the mother cell. This reduces the metabolic potential of the forespore, which becomes dependent on mother cell metabolism and the SpoIIQ–SpoIIIA channel to obtain metabolic building blocks necessary for development. We demonstrate that metabolic differentiation depends on the ClpCP protease and a forespore-produced protein encoded by the yjbA gene, which we have renamed MdfA (metabolic differentiation factor A). MdfA is conserved in aerobic endospore formers and required for spore resistance to hypochlorite. Using mass spectrometry and quantitative fluorescence microscopy, we show that MdfA mediates the depletion of dozens of metabolic enzymes and key transcription factors from the forespore. An accompanying study by Massoni and colleagues demonstrates that MdfA is a ClpC adaptor protein that directly interacts with and stimulates ClpCP activity. Together, these results document a developmentally regulated proteolytic pathway that reshapes forespore metabolism, reinforces differentiation, and enhances spore resistance to the oxidant hypochlorite.
{"title":"Developmentally regulated proteolysis by MdfA and ClpCP mediates metabolic differentiation during Bacillus subtilis sporulation","authors":"Eammon P. Riley, Jelani A. Lyda, Octavio Reyes-Matte, Joseph Sugie, Iqra R. Kasu, Eray Enustun, Emily G. Armbruster, Sumedha Ravishankar, Rivka L. Isaacson, Amy H. Camp, Javier Lopez-Garrido, Kit Pogliano","doi":"10.1101/gad.352535.124","DOIUrl":"https://doi.org/10.1101/gad.352535.124","url":null,"abstract":"<em>Bacillus subtilis</em> sporulation entails a dramatic transformation of the two cells required to assemble a dormant spore, with the larger mother cell engulfing the smaller forespore to produce the “cell within a cell” structure that is a hallmark of endospore formation. Sporulation also entails metabolic differentiation, whereby key metabolic enzymes are depleted from the forespore but maintained in the mother cell. This reduces the metabolic potential of the forespore, which becomes dependent on mother cell metabolism and the SpoIIQ–SpoIIIA channel to obtain metabolic building blocks necessary for development. We demonstrate that metabolic differentiation depends on the ClpCP protease and a forespore-produced protein encoded by the <em>yjbA</em> gene, which we have renamed MdfA (metabolic differentiation factor A). MdfA is conserved in aerobic endospore formers and required for spore resistance to hypochlorite. Using mass spectrometry and quantitative fluorescence microscopy, we show that MdfA mediates the depletion of dozens of metabolic enzymes and key transcription factors from the forespore. An accompanying study by Massoni and colleagues demonstrates that MdfA is a ClpC adaptor protein that directly interacts with and stimulates ClpCP activity. Together, these results document a developmentally regulated proteolytic pathway that reshapes forespore metabolism, reinforces differentiation, and enhances spore resistance to the oxidant hypochlorite.","PeriodicalId":12591,"journal":{"name":"Genes & development","volume":"23 1","pages":""},"PeriodicalIF":10.5,"publicationDate":"2025-03-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143627423","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Annika Martin, Johannes Schabort, Rebecca Bartke-Croughan, Stella Tran, Atul Preetham, Robert Lu, Richard Ho, Jianpu Gao, Shirin Jenkins, John Boyle, George E. Ghanim, Milind Jagota, Yun S. Song, Hanqin Li, Dirk Hockemeyer
Mutations in the shelterin protein POT1 are associated with diverse cancers and thought to drive carcinogenesis by impairing POT1's suppression of aberrant telomere elongation. To classify clinical variants of uncertain significance (VUSs) and identify cancer-driving loss-of-function mutations, we developed a locally haploid human stem cell system to evaluate >1900 POT1 mutations, including >600 VUSs. Unexpectedly, many validated familial cancer-associated POT1 (caPOT1) mutations are haplosufficient for cellular viability, indicating that some pathogenic alleles do not act through a loss-of-function mechanism. Instead, POT1's DNA damage response suppression and telomere length control are genetically separable. ATR inhibition enables isolation of frameshift mutants, demonstrating that the only essential function of POT1 is to repress ATR. Furthermore, comparison of caPOT1 and frameshift alleles reveals a class of caPOT1 mutations that elongate telomeres more rapidly than full loss-of-function alleles. This telomere length-promoting activity is independent from POT1's role in overhang sequestration and fill-in synthesis.
{"title":"Active telomere elongation by a subclass of cancer-associated POT1 mutations","authors":"Annika Martin, Johannes Schabort, Rebecca Bartke-Croughan, Stella Tran, Atul Preetham, Robert Lu, Richard Ho, Jianpu Gao, Shirin Jenkins, John Boyle, George E. Ghanim, Milind Jagota, Yun S. Song, Hanqin Li, Dirk Hockemeyer","doi":"10.1101/gad.352492.124","DOIUrl":"https://doi.org/10.1101/gad.352492.124","url":null,"abstract":"Mutations in the shelterin protein POT1 are associated with diverse cancers and thought to drive carcinogenesis by impairing POT1's suppression of aberrant telomere elongation. To classify clinical variants of uncertain significance (VUSs) and identify cancer-driving loss-of-function mutations, we developed a locally haploid human stem cell system to evaluate >1900 POT1 mutations, including >600 VUSs. Unexpectedly, many validated familial cancer-associated POT1 (caPOT1) mutations are haplosufficient for cellular viability, indicating that some pathogenic alleles do not act through a loss-of-function mechanism. Instead, POT1's DNA damage response suppression and telomere length control are genetically separable. ATR inhibition enables isolation of frameshift mutants, demonstrating that the only essential function of POT1 is to repress ATR. Furthermore, comparison of caPOT1 and frameshift alleles reveals a class of caPOT1 mutations that elongate telomeres more rapidly than full loss-of-function alleles. This telomere length-promoting activity is independent from POT1's role in overhang sequestration and fill-in synthesis.","PeriodicalId":12591,"journal":{"name":"Genes & development","volume":"9 1","pages":""},"PeriodicalIF":10.5,"publicationDate":"2025-02-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143518779","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Clara Hermant, Carlos Michel Mourra-Díaz, Marlies E. Oomen, Luis Altamirano-Pacheco, Mrinmoy Pal, Tsunetoshi Nakatani, Maria-Elena Torres-Padilla
The regulatory circuitry of cell-specific transcriptional programs is thought to be influenced by transposable elements (TEs), whereby TEs serve as raw material for the diversification and genome-wide distribution of genetic elements that contain cis-regulatory activity. However, the transcriptional activators of TEs in relevant physiological contexts are largely unknown. Here, we undertook an evolutionary approach to identify regulators of two main families of MERVL, a major regulator of transcription during early mouse development. Using a combination of phyloregulatory, transcriptomic, and loss-of-function approaches, we demonstrate that SRF is a novel regulator of MERVL and embryonic transcription during zygotic genome activation. By resolving the phylogenetic history of two major MERVL families, we delineate the evolutionary acquisition of SRF and DUX binding sites and show that the acquisition of the SRF site precedes that of DUX. SRF contributes to embryonic transcription through the regulation of MERVLs, which in turn serve as promoters for host genes. Our work identifies new transcriptional regulators and TEs that shape the gene expression programs in early embryos and highlights the process of TE domestication via the sequential acquisition of transcription factor binding sites and coevolution with the host.
{"title":"The transcription factor SRF regulates MERVL retrotransposons and gene expression during zygotic genome activation","authors":"Clara Hermant, Carlos Michel Mourra-Díaz, Marlies E. Oomen, Luis Altamirano-Pacheco, Mrinmoy Pal, Tsunetoshi Nakatani, Maria-Elena Torres-Padilla","doi":"10.1101/gad.352270.124","DOIUrl":"https://doi.org/10.1101/gad.352270.124","url":null,"abstract":"The regulatory circuitry of cell-specific transcriptional programs is thought to be influenced by transposable elements (TEs), whereby TEs serve as raw material for the diversification and genome-wide distribution of genetic elements that contain <em>cis</em>-regulatory activity. However, the transcriptional activators of TEs in relevant physiological contexts are largely unknown. Here, we undertook an evolutionary approach to identify regulators of two main families of MERVL, a major regulator of transcription during early mouse development. Using a combination of phyloregulatory, transcriptomic, and loss-of-function approaches, we demonstrate that SRF is a novel regulator of MERVL and embryonic transcription during zygotic genome activation. By resolving the phylogenetic history of two major MERVL families, we delineate the evolutionary acquisition of SRF and DUX binding sites and show that the acquisition of the SRF site precedes that of DUX. SRF contributes to embryonic transcription through the regulation of MERVLs, which in turn serve as promoters for host genes. Our work identifies new transcriptional regulators and TEs that shape the gene expression programs in early embryos and highlights the process of TE domestication via the sequential acquisition of transcription factor binding sites and coevolution with the host.","PeriodicalId":12591,"journal":{"name":"Genes & development","volume":"52 1","pages":""},"PeriodicalIF":10.5,"publicationDate":"2025-02-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143518777","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Ana Chocarro-Calvo, Miguel Jociles-Ortega, José Manuel García-Martinez, Pakavarin Louphrasitthiphol, Sofia Carvalho-Marques, Yurena Vivas-García, Ana Ramírez-Sánchez, Jagat Chauhan, M. Carmen Fiuza, Manuel Druan, Adriana Sánchez-Danés, Colin R. Goding, Custodia García-Jiménez
Interaction between the tumor microenvironment and cancer cell plasticity drives intratumor phenotypic heterogeneity and underpins disease progression and nongenetic therapy resistance. Phenotype-specific expression of the AXL receptor tyrosine kinase is a pivotal player in dormancy, invasion, and resistance to treatment. However, although the AXL ligand GAS6 is present within tumors, how AXL is activated in metastasizing cells remains unclear. Here, using melanoma as a model, we reveal that AXL is activated by exposure to human adipocytes and to oleic acid, a monounsaturated fatty acid abundant in lymph and in adipocytes. AXL activation triggers SRC-dependent formation and nuclear translocation of a β-catenin–CAV1 complex required for melanoma invasiveness. Remarkably, only undifferentiated AXLHigh melanoma cells engage in symbiosis with human adipocytes, in part by triggering WNT5a-mediated lipolysis, leading to AXL-dependent, but FATP-independent, fatty acid uptake and nuclear localization of the β-catenin–CAV1 complex. Significantly, human melanomas in the vicinity of adipocytes exhibit high levels of nuclear CAV1. The results unveil an AXL- and CAV1-dependent mechanism through which a nutritional input drives phenotype-specific activation of a prometastasis program. Given the key role of AXL in a broad range of cancers, the results offer major insights into the mechanisms of cancer cell dormancy and therapy resistance.
{"title":"Fatty acid uptake activates an AXL–CAV1–β-catenin axis to drive melanoma progression","authors":"Ana Chocarro-Calvo, Miguel Jociles-Ortega, José Manuel García-Martinez, Pakavarin Louphrasitthiphol, Sofia Carvalho-Marques, Yurena Vivas-García, Ana Ramírez-Sánchez, Jagat Chauhan, M. Carmen Fiuza, Manuel Druan, Adriana Sánchez-Danés, Colin R. Goding, Custodia García-Jiménez","doi":"10.1101/gad.351985.124","DOIUrl":"https://doi.org/10.1101/gad.351985.124","url":null,"abstract":"Interaction between the tumor microenvironment and cancer cell plasticity drives intratumor phenotypic heterogeneity and underpins disease progression and nongenetic therapy resistance. Phenotype-specific expression of the AXL receptor tyrosine kinase is a pivotal player in dormancy, invasion, and resistance to treatment. However, although the AXL ligand GAS6 is present within tumors, how AXL is activated in metastasizing cells remains unclear. Here, using melanoma as a model, we reveal that AXL is activated by exposure to human adipocytes and to oleic acid, a monounsaturated fatty acid abundant in lymph and in adipocytes. AXL activation triggers SRC-dependent formation and nuclear translocation of a β-catenin–CAV1 complex required for melanoma invasiveness. Remarkably, only undifferentiated AXL<sup>High</sup> melanoma cells engage in symbiosis with human adipocytes, in part by triggering WNT5a-mediated lipolysis, leading to AXL-dependent, but FATP-independent, fatty acid uptake and nuclear localization of the β-catenin–CAV1 complex. Significantly, human melanomas in the vicinity of adipocytes exhibit high levels of nuclear CAV1. The results unveil an AXL- and CAV1-dependent mechanism through which a nutritional input drives phenotype-specific activation of a prometastasis program. Given the key role of AXL in a broad range of cancers, the results offer major insights into the mechanisms of cancer cell dormancy and therapy resistance.","PeriodicalId":12591,"journal":{"name":"Genes & development","volume":"33 1","pages":""},"PeriodicalIF":10.5,"publicationDate":"2025-02-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143518776","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Alternative splicing (AS) is regulated by a myriad of RNA-binding proteins (RBPs) in a coordinated manner. However, most studies characterize RBPs individually. In this issue of Genes & Development, Peyda and colleagues (doi:10.1101/gad.352105.124) revealed how the LASR complex, consisting of multiple RBPs, regulates AS by recognizing multipart sequences. Their approach may be applicable to studying the combinatorial effects of other RBPs, which is critical for cracking the splicing code.
{"title":"RNA-binding proteins: it's better to play in a band","authors":"Joshua Jeong, Klemens J. Hertel, Yongsheng Shi","doi":"10.1101/gad.352667.125","DOIUrl":"https://doi.org/10.1101/gad.352667.125","url":null,"abstract":"Alternative splicing (AS) is regulated by a myriad of RNA-binding proteins (RBPs) in a coordinated manner. However, most studies characterize RBPs individually. In this issue of <em>Genes & Development</em>, Peyda and colleagues (doi:10.1101/gad.352105.124) revealed how the LASR complex, consisting of multiple RBPs, regulates AS by recognizing multipart sequences. Their approach may be applicable to studying the combinatorial effects of other RBPs, which is critical for cracking the splicing code.","PeriodicalId":12591,"journal":{"name":"Genes & development","volume":"10 1","pages":""},"PeriodicalIF":10.5,"publicationDate":"2025-02-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143401581","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Joyce Wolf van der Meer, Axelle Larue, Jan A. van der Knaap, Gillian E. Chalkley, Ayestha Sijm, Leila Beikmohammadi, Elena N. Kozhevnikova, Aniek van der Vaart, Ben C. Tilly, Karel Bezstarosti, Dick H.W. Dekkers, Wouter A.S. Doff, P. Jantine van de Wetering-Tieleman, Kristina Lanko, Tahsin Stefan Barakat, Tim Allertz, Jeffrey van Haren, Jeroen A.A. Demmers, Yaser Atlasi, C. Peter Verrijzer
Pathogenic variants in the ubiquitin-specific protease 7 (USP7) gene cause a neurodevelopmental disorder called Hao-Fountain syndrome. However, it remains unclear which of USP7's pleiotropic functions are relevant for neurodevelopment. Here, we present a combination of quantitative proteomics, transcriptomics, and epigenomics to define the USP7 regulatory circuitry during neuronal differentiation. USP7 activity is required for the transcriptional programs that direct both the differentiation of embryonic stem cells into neural stem cells and the neuronal differentiation of SH-SY5Y neuroblastoma cells. USP7 controls the dosage of the Polycomb monubiquitylated histone H2A lysine 119 (H2AK119ub1) ubiquitin ligase complexes ncPRC1.1 and ncPRC1.6. Loss-of-function experiments revealed that BCOR–ncPRC1.1, but not ncPRC1.6, is a key effector of USP7 during neuronal differentiation. Indeed, BCOR–ncPRC1.1 mediates a major portion of USP7-dependent gene regulation during this process. Besides providing a detailed map of the USP7 regulome during neurodifferentiation, our results suggest that USP7- and ncPRC1.1-associated neurodevelopmental disorders involve dysregulation of a shared epigenetic network.
{"title":"Hao-Fountain syndrome protein USP7 controls neuronal differentiation via BCOR–ncPRC1.1","authors":"Joyce Wolf van der Meer, Axelle Larue, Jan A. van der Knaap, Gillian E. Chalkley, Ayestha Sijm, Leila Beikmohammadi, Elena N. Kozhevnikova, Aniek van der Vaart, Ben C. Tilly, Karel Bezstarosti, Dick H.W. Dekkers, Wouter A.S. Doff, P. Jantine van de Wetering-Tieleman, Kristina Lanko, Tahsin Stefan Barakat, Tim Allertz, Jeffrey van Haren, Jeroen A.A. Demmers, Yaser Atlasi, C. Peter Verrijzer","doi":"10.1101/gad.352272.124","DOIUrl":"https://doi.org/10.1101/gad.352272.124","url":null,"abstract":"Pathogenic variants in the ubiquitin-specific protease 7 (<em>USP7</em>) gene cause a neurodevelopmental disorder called Hao-Fountain syndrome. However, it remains unclear which of USP7's pleiotropic functions are relevant for neurodevelopment. Here, we present a combination of quantitative proteomics, transcriptomics, and epigenomics to define the USP7 regulatory circuitry during neuronal differentiation. USP7 activity is required for the transcriptional programs that direct both the differentiation of embryonic stem cells into neural stem cells and the neuronal differentiation of SH-SY5Y neuroblastoma cells. USP7 controls the dosage of the Polycomb monubiquitylated histone H2A lysine 119 (H2AK119ub1) ubiquitin ligase complexes ncPRC1.1 and ncPRC1.6. Loss-of-function experiments revealed that BCOR–ncPRC1.1, but not ncPRC1.6, is a key effector of USP7 during neuronal differentiation. Indeed, BCOR–ncPRC1.1 mediates a major portion of USP7-dependent gene regulation during this process. Besides providing a detailed map of the USP7 regulome during neurodifferentiation, our results suggest that USP7- and ncPRC1.1-associated neurodevelopmental disorders involve dysregulation of a shared epigenetic network.","PeriodicalId":12591,"journal":{"name":"Genes & development","volume":"15 1","pages":""},"PeriodicalIF":10.5,"publicationDate":"2025-02-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143367421","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
京公网安备 11010802042870号
京ICP备2023020795号-1
扫码关注我们
求助内容：
应助结果提醒方式：